Gastric cancer accounts for approximately 13,000 deaths in the United States. The pathology of gastric cancer is characterized by diverse histology between and within tumors, and the variable presence of necrosis , lymphocytic infiltration, and stroma. In many tumors, the carcinoma cells comprise only a minority of the total population, and it is likely that many genetic alterations are obscured by the overwhelming contamination from normal cells. Similarly, the genetic analysis of potential pre-neoplastic gastric lesions is complicated by the overwhelming numbers of normal mucosal and stromal cells. A new method which can analyze specific and small numbers of cells has been developed in my laboratory to overcome the above difficulties. The method involves the selective destruction and protection of DNA present on a microscope slide by ultraviolet radiation followed by PCR mediated analysis. Preliminary data suggests a resolution of approximately 50 cells with a theoretic ability to analyze one cell. This novel technique will be further developed and employed to detect mutations and loss of heterozygosity of the K-ras, retinoblastoma, p53 genes, and other alterations in gastric cancers. The method should allow the detection of these mutations in any gastric cancer regardless of its stromal contamination. Tumor progression of individual tumors will be directly studied by determining the topography of the primary mutations in adjacent dysplastic, metaplastic, and normal mucosa. The location of each mutation should provide an estimate of their relative contribution to the malignancy. The ultimate goal is a greater understanding of the timing and extent of the molecular events in gastric cancer.